This application presents our overall plan to investigate the cellular and molecular basis of the increased autoantibody response of old mice. The first aim is to understand the cellular basis of autoantibody production in old mice. The increased spontaneous production of autoantibodies by conventional, non-autoimmune, non-immunized old mice is associated with significant changes in the distribution of lymphocytes. We found increased numbers of peritoneal cells, Ly1-bearing B cells, and low density, activated lymphocytes in old mice. The contribution of these lymphoid populations to the increased production of autoantibodies by old mice will be studied. The second aim is to determine if long-lived peripheral T cells in old mice are responsible for the selection of the autoantibody B cell repertoire. It has been found that the level of autoanti- idiotypic antibody, one of the autoantibodies produced in greater quantity in old as compared to young mice, is regulated by peripheral T cells in old mice. These cells appear to select B cells of this specificity in the absence of antigen, perhaps through idiotype-anti-idiotypic interactions. The role of peripheral T cells from old mice on the selection of the B cells specific for autoantibodies to erythrocytes, thyroglobulin, DNA and immunoglobulin will be investigated. The third aim is to examine the utilization of the immunoglobulin heavy chain variable region (VH) gene families by autoantibody forming cells in old mice. The increased number of activated and Ly1-bearing B cells in old mice is similar to that found in neonatal mice, as is the increased representation of autoantibodies, autoanti-idiotypic antibodies multi-reactive antibodies and antibodies with high "connectivity" within the B cell repertoire. Recently, fetal and neonatal mice have been found to utilize preferentially the most D-proximal VH gene families. The utilization of heavy chain variable region genes by B cells, in general, from old mice and autoantibody producing B cells from old mice in particular will be determined.